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<p>Mitochondrial DNA (mtDNA) mutations are a major cause of sensorineural hearing loss (SNHL). The m.1555A &gt;G mutation in the mitochondrial 12S rRNA gene is closely linked to nonsyndromic and aminoglycoside-induced hearing loss, leading to impaired oxidative phosphorylation (OXPHOS) and ATP production. Current treatments focus on auditory rehabilitation without addressing mitochondrial pathology. This study investigated mitochondrial transplantation as a therapeutic approach. Fibroblasts from two patients with homoplasmic m.1555A &gt; G mutations identified during cochlear implant surgery received allogeneic mitochondria (PN-101) derived from human umbilical cord mesenchymal stem cells. Transplantation significantly increased intracellular ATP levels, complex I activity, and OXPHOS protein expression, while protecting against kanamycin-induced mitochondrial dysfunction. Importantly, PN-101 induced a heteroplasmy shift toward wild-type mtDNA, with repeated treatments sustaining and enhancing this effect. These findings demonstrate that PN-101–mediated mitochondrial transplantation improves mitochondrial bioenergetics and modulates mtDNA heteroplasmy in m.1555A &gt; G mutant cells, suggesting a promising disease-modifying therapy for mtDNA-related hearing loss and a potential precision medicine approach.</p>

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Therapeutic potential of mitochondrial transfer in reversing mutant-to-wild-type mtDNA ratio and improving mitochondrial dysfunction in 1555A>G mtDNA mutation-associated hearing loss

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Yujin Kim,
  • Chang-Hee Kim,
  • Dong Woo Nam,
  • Bong Jik Kim,
  • Ngoc-Trinh Tran,
  • Jin Hee Han,
  • Minyoung Kim,
  • Shin-Hye Yu,
  • Seo-Eun Lee,
  • Jeong Seon Yeo,
  • Iksun Kwon,
  • Kyuboem Han,
  • Chun-Hyung Kim,
  • Young Cheol Kang,
  • Byung Yoon Choi

摘要

Mitochondrial DNA (mtDNA) mutations are a major cause of sensorineural hearing loss (SNHL). The m.1555A >G mutation in the mitochondrial 12S rRNA gene is closely linked to nonsyndromic and aminoglycoside-induced hearing loss, leading to impaired oxidative phosphorylation (OXPHOS) and ATP production. Current treatments focus on auditory rehabilitation without addressing mitochondrial pathology. This study investigated mitochondrial transplantation as a therapeutic approach. Fibroblasts from two patients with homoplasmic m.1555A > G mutations identified during cochlear implant surgery received allogeneic mitochondria (PN-101) derived from human umbilical cord mesenchymal stem cells. Transplantation significantly increased intracellular ATP levels, complex I activity, and OXPHOS protein expression, while protecting against kanamycin-induced mitochondrial dysfunction. Importantly, PN-101 induced a heteroplasmy shift toward wild-type mtDNA, with repeated treatments sustaining and enhancing this effect. These findings demonstrate that PN-101–mediated mitochondrial transplantation improves mitochondrial bioenergetics and modulates mtDNA heteroplasmy in m.1555A > G mutant cells, suggesting a promising disease-modifying therapy for mtDNA-related hearing loss and a potential precision medicine approach.